Patent GB-1290686-A (GB)
IPC: C07D457/04
Filed: 1969-09-16
Abstract: 1290686 Lysergic acid derivatives INSTITUT PASTEUR 16 Sept 1969 [17 Sept 1968 31 July 1969] 45587/69 Heading C2C Compounds I in which R is 1-12 C alkyl or aminoalkyl, cycloalkyl or 6-18 C aryl; R<SP>1</SP> is H or 1-5 C alkyl; R<SP>2</SP> is 1-4 C alkyl or phenyl and R<SP>3</SP> is H, 1-4 C alkyl, 2-4 C alkenyl or benzyl or COOR may be replaced by an amide grouping are prepared by cyclization of compounds II in which X and X<SP>1</SP> are H or halo, at least one being halo using an alkali metal amide or 1-4 C alkyl alkali metal and carrying out the reaction at - 33‹ to + 50‹ C. Compounds I where R<SP>1</SP> is 1-5 C alkyl are claimed per se. Methyl 6 - [5<SP>1</SP>- bromo - isatylidene - methylidene]-nicotinate (1) is prepared by reaction of methyl 6-methylnicotinate, with 5-bromoisatin. Methyl 6 - [5<SP>1</SP> - bromo - 21 - oxo - indol - 31- yl)-methylene]-nicotinate (2) is prepared by reduction of (1) using Zn/CH 3 COOH. Methyl 6- [(21,31 - dihydro - 5<SP>1</SP> - bromo - indol - 3<SP>1</SP> -  yl)- methylene]nicotinate (3) is prepared by reaction of (2) with diborane. Methyl 6-[(1<SP>1</SP>-acetyl-2<SP>1</SP>,3<SP>1</SP>- dihydro - 5<SP>1</SP> - bromo - indol - 3<SP>1</SP> - yl) - methylene nicotinate (4) is prepared by reaction of (3) with acetic anhydride. Methyl 6-[(5<SP>1</SP>-bromo-indol-3- yl)-methylene]nicotinate (5) is prepared by reaction of (3) with MnO 2 . The iodomethylate of (5) is prepared by reaction of (5) with CH 3 I. Methyl 1 - methyl - 6 - [(51 - bromo - 3<SP>1 </SP>- indolyl)- methylene] - 1,2,5,6 - tetrahydronicotinate (6) is prepared by reduction of the iodomethylate of (5) with KBH 4 . 6-[(5<SP>1</SP>-Bromo-indol-3<SP>1</SP>-yl)methylene]-N,N-diethyl-nicotinamide (7) is prepared by reacting (5) with diethylamine. Methyl 6- [(1<SP>1</SP> - acetyl 2<SP>1</SP>,3<SP>1</SP> - dihydro - 5<SP>1</SP> - bromo - 3<SP>1</SP> - indolyl)-methylene]nicotinate iodomethylate (8) is prepared by reacting (4) with CH 3 I. Methyl 1- methyl - 6 - [(1<SP>1</SP> - acetyl - 2<SP>1</SP>,3<SP>1</SP> - dihydro - 5<SP>1</SP>- bromo - 3<SP>1</SP> - indolyl)methylene] - 1,2,5,6 - tetrahydro-nicotinate (9) is prepared by reacting (8) with KBH 4  and this may be deacetylated with HCl/MeOH. Methyl 6-[(2<SP>1</SP>-ozoindol-3<SP>1</SP>-yl)-methylene]nicotinate (10) is prepared by debromination of (2). Methyl 6.[(2<SP>1</SP>,3<SP>1</SP>-dihydro-indol-3<SP>1</SP>-yl)- methylene]-nicotinate (11) is prepared by reacting (10) with diborane. Methyl 6-[(1<SP>1</SP>-acetyl-2<SP>1</SP>,3<SP>1</SP>- dihydro - 31 - indolyl) -methylene] - nicotinate (12) is prepared by acetylation of (11). Methyl 6-[(3<SP>1</SP>- indolyl)-methylene]-nicotinate (12) is prepared by reacting (11) with MnO 2 . Methyl 6-[(3<SP>1</SP>-indoly)- methylene]nicotinate iodomethylate (14) is prepared by reacting (13) with CH 3 I. Methyl 6- [(31 - indolyl)methylene] - 1   - methyl - 1,2,5,6- tetrahydronicotinate is prepared by reaction of (13) with KBH 4 . 1-Methyl-6-[(5<SP>1</SP>-bromo-3<SP>1</SP>-indolyl)methylene] - 1,2,5,6 - tetrahydro - N,N - diethylnicotinamide and 6 - [(3<SP>1</SP> - indolyl)methylene]-N,N-diethylnicotinamide are also isolated as intermediates.